Control of cellular proliferation is of great importance for many normal and abnormal biological processes; including development, wound healing, programmed cell death, angiogenesis and tumorigenesis. A myriad of components involved in the regulation of cell proliferation have been identified, including growth factors, cell cycle regulators, oncogenes and tumor suppressor genes. One of the less well-understood aspects of oncogenesis is the change in glycosylation of certain polypeptides.
The transfer of glycosyl residues from nucleotide-activated sugar molecules to other carbohydrates or to peptides is catalyzed by glycosyltransferases, whose specificity is restricted to the formation of a single glycosidic bond linking two specific sugar residues or a sugar residue to an aglycone. The cell and tissue-specific expression of glycosyltransferases depends on the differentiation, development and malignant transformation of the cell.
Aberrant glycosylationof glycosphingolipids and glycoproteins in tumor cells has been implicated as an essential mechanism in defining stage, direction, and fate of tumor progression. Clinical studies have shown a clear correlation between aberrant glycosylation status of primary tumor and invasive/metastatic potential of human cancer as reflected by 5- or 10-year survival rates of patients. Carbohydrates expressed in tumor cells may be adhesion molecules, or may modulate adhesion receptor function. Some are known to be directly involved in cell adhesion, and are recognized by selectins or other carbohydrate-binding proteins, or by complementary carbohydrates. N- or O-glycosylation of functionally important membrane components may alter tumor cell adhesion or motility in a direction that either promotes or inhibits invasion and metastasis. Examples of such receptors are E-cadherin, integrins, immunoglobulin family receptors, e.g. CD44, and lysosome-associated membrane protein.
Alternatively, gangliosides and sphingolipids may modulate transmembrane signaling essential for tumor cell growth, invasion, and metastasis. The transducer molecules susceptible to gangliosides and sphingolipids include integrin receptors, tyrosine kinase-linked growth factor receptors, protein kinase C, and G-protein-linked receptor affecting protein kinase A. Some glycosphingolipids (e.g., Gb3Cer, Le(y), ceramide, and sphingosine induce tumor cell differentiation and subsequent apoptosis. A crucial mechanism for inhibition of metastasis may involve blocking of transmembrane signaling for expression of P- and E-selectin.
One substrate for glycosyltransferases are mucins, which are heavily glycosylated high molecular weight glycoproteins. In epithelial cancers such as colorectal cancer, both qualitative and quantitative alterations in carbohydrate and polypeptide moieties of mucin glycoproteins occur. These changes in mucin glycoproteins are one of the most common phenotypic markers of colorectal carcinogenesis and may play an important pathobiological role. The increased exposure of peptide epitopes of mucin glycoproteins in colorectal cancer appears to be due to either abnormal glycosylation or altered levels of mucin gene transcription.
Alteration of cell surface carbohydrate antigens during malignant transformation is a well-known phenomenon observed in various tumors. In prostatic carcinoma, nearly total deletion of normally occurring ABO and type I-based Lewis antigens, Le(a) and Leb, has been observed in several studies. Experimental results suggest an alteration in glycosyl transferase activity in prostatic carcinoma, with preserved or increased activity of enzymes responsible for the synthesis of the type II core sequence. During the transformation of normal cells to colon carcinoma cells, there is an increase in the presence of mucin carbohydrate moieties that are not detectable in normal cells.
The identification of proteins involved with tumor growth and metastasis is of great interest for clinical and research purposes. Understanding the involvement of glycosyl transferases, and the effect of specific changes in the glycosylation of their substrates may provide new therapeutic approaches.